tbuckley/cabot-search huggingface dataset:
Abstract 3957: Receptor Activator of NF-κB (RANK) confers resistance to chemotherapy in AML and associates with dismal disease course
Authors: Kim L. Clar, Lisa M. Weber, Bastian J. Schmied, Jonas S. Heitmann, Maddalena Marconato, Claudia Tandler, Pascal Schneider, Helmut R. Salih
Journal: Cancer Research (2022)

Abstract Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Untreated, AML leads to death within months after first symptoms. Combinatorial chemotherapy, mostly using a pyrimidine analog together with an anthracycline, made this previously incurable disease medicable, and response to remission-inducing chemotherapy strongly correlates with patient outcome. Despite advances in treatment over the recent years, AML still has a poor prognosis with an average 5-year survival rate of 30%. A better understanding of the molecular mechanisms predicting and affecting treatment efficacy is key to improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on the primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of the cytokines IL-6, IL-8, TNF and IL-10 acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, prevalence of RANK expression on leukemic cells correlated with dismal disease course of patients as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment. Moreover, the association of RANK expression with adverse disease course identifies RANK as potential “functional” prognostic marker and putative target for therapeutic intervention to improve treatment response of AML patients. Citation Format: Kim L. Clar, Lisa M. Weber, Bastian J. Schmied, Jonas S. Heitmann, Maddalena Marconato, Claudia Tandler, Pascal Schneider, Helmut R. Salih. Receptor Activator of NF-κB (RANK) confers resistance to chemotherapy in AML and associates with dismal disease course [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3957.
Abstract 828: Screen for actionable ERBB3 mutations
Authors: Marika K. Koivu, Deepankar Chakroborty, Kari J. Kurppa, Klaus Elenius
Journal: Cancer Research (2022)

Abstract Activating mutations and copy number variations in ERBB genes have been shown to serve as oncogenic driver mutations and predictive biomarkers for ERBB inhibitor drugs. To address whether mutations in ERBB3 can affect the potential of ERBB3 to promote growth or affect sensitivity to ERBB inhibitors, we set up an unbiased functional screen for ERBB3 missense or nonsense mutations in the context of ERBB2/ERBB3 heterodimers. To this end, the iSCREAM (in vitro screen of activating mutations) pipeline, recently developed in our laboratory, was chosen. This platform exploits randomly mutated cDNA libraries of the gene of interest created with error-prone PCR and allows an unbiased assessment of growth-advantage conferred by thousands of mutations in parallel. To set up the model for screening actionable ERBB3 mutations, interleukin-3 (IL-3)-dependent Ba/F3 cells were engineered to express a homodimerization-incompetent ERBB2 V956R mutant together with ERBB3 constructs. The model was validated to serve as a readout for ERBB3's ability in activating ERBB2 kinase by demonstrating that cells expressing known transforming ERBB3 mutations, together with ERBB2 V956R, survived and expanded in the absence of IL-3. In contrast, control cells expressing ERBB2 V956R together with wild-type ERBB3 rapidly died in the absence of IL-3. The cell background with ERBB2 V956R expression was subsequently used as a target for retroviral expression of a cDNA library of randomly mutated ERBB3 constructs. The cells harboring activating ERBB3 mutations were allowed to evolve for 15-48 days. The identity of the mutations was determined from the surviving cell population by ERBB3-targeted next generation sequencing. The discovered activating mutations were validated by cloning them into expression vectors and addressing their activity by Western analyses and growth assays in Ba/F3, NIH-3T3, and MCF10A cell backgrounds. As a demonstration of the validity of the protocol, the well-characterized activating ERBB3 mutation ERBB3 E928G was identified as one of the major hits. These analyses are expected to identify activating ERBB3 mutations that are directly actionable or that provide predictive value for the use of drugs targeting ERBB signaling. Citation Format: Marika K. Koivu, Deepankar Chakroborty, Kari J. Kurppa, Klaus Elenius. Screen for actionable ERBB3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 828.
Abstract 5880: Diabetes incidence after obesity-related cancer diagnosis and survival in the women’s health initiative
Authors: Prasoona Karra, Maci Winn, Benjamin Haaland, Garnet Anderson, Cynthia A. Thomson, Aladdin H. Shadyab, Juhua Luo, Nazmus Saquib, Howard Strickler, Rowan Chlebowski, Rhonda Arthur, Sheetal Hardikar, Mary C. Playdon
Journal: Cancer Research (2022)

Abstract Introduction: Obesity-related cancer (ORC) diagnosed individuals are at an elevated risk of new-onset diabetes compared with cancer-free individuals. However, less is known about mortality among those with incident type 2 diabetes after cancer. Methods: In the Women’s Health Initiative (N=14,455 ORC cases), we measured the association of incident type 2 diabetes diagnosed 0-1 years, &amp;gt;1-3, &amp;gt;3-5, &amp;gt;5-7 and &amp;gt;7-10 years after ORC diagnosis with cancer-specific and overall mortality using stratified Cox proportional hazards regression analysis. Results: The participants were post-menopausal females with ORC and predominantly white. The number of WHI participants with ORC who developed diabetes after cancer diagnosis were: 0-1 years - 205/12992 (1.58%); 1-3 years - 326/11322 (2.88%); 3-5 years - 276/9784 (2.82%); 5-7 years - 268/8420 (3.18%); and 7-10 years - 510/6419 (7.95%). The median survival after the first year of cancer diagnosis for participants without diabetes was 16.6 years (95% CI: 16.17-17.0 years) and for those with diabetes was 10.3 years (95% CI: 7.97-14.9 years). New-onset diabetes after ORC diagnosis showed elevated overall mortality and cancer-specific mortality when compared with no diabetes diagnosis. Conclusions: Incident type 2 diabetes is associated with worse cancer-specific and overall survival, particularly in the year after diagnosis, among women with ORC. Type 2 Diabetes from time since cancer diagnosis Overall mortality HR (95% CI)a Cancer-specific mortality HR (95% CI)a 0-1 years 1.79 (1.41-2.29) 1.56 (1.04-2.34) &amp;gt;1-3 years 1.22 (0.99-1.51) 1.05 (0.72-1.55) &amp;gt;3-5 years 1.21 (0.95-1.55) 1.37 (0.89-2.12) &amp;gt;5-7 years 1.02 (0.78-1.33) 0.80 (0.47-1.36) &amp;gt;7-10 years 1.10 (0.87-1.40) 0.97 (0.59-1.60) aModel adjusted for demographics (age, education, race/ethnicity, marital status), body mass index (BMI)) and cancer characteristics (cancer type, stage, grade). CI = confidence interval; HR = Hazard ratio. Citation Format: Prasoona Karra, Maci Winn, Benjamin Haaland, Garnet Anderson, Cynthia A. Thomson, Aladdin H. Shadyab, Juhua Luo, Nazmus Saquib, Howard Strickler, Rowan Chlebowski, Rhonda Arthur, Sheetal Hardikar, Mary C. Playdon. Diabetes incidence after obesity-related cancer diagnosis and survival in the women’s health initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5880.
Abstract 5286: RNase7-guided anti-ROS1 targeted therapy for hepatocellular carcinoma
Authors: Chunxiao Liu, Zhengyu Zha, Chenhao Zhou, Dihua Yu, Ning Ren, Mien-Chien Hung
Journal: Cancer Research (2022)

Abstract Oncogenic activation of c-ros oncogene 1 (ROS1) kinase due to gene fusion by chromosomal rearrangements was found in multiple cancers. The anti-ROS1 fusion gene is a successful therapeutic target with a 72% objective response rate in ROS1-rearranged NSCLC patients. However, it has yet to be determined whether wild-type ROS1 plays a role in cancer development or could serve as a therapeutic target as its ligand was unknown. Our study unexpectedly identified that RNase7, a RNase superfamily protein, is specifically pulled down by ROS1 and acts as a ROS1 ligand. In HCC patient-derived xenograft and an orthotopic mouse model of HCC, we found that crizotinib, an FDA-approved ROS1 inhibitor, exhibits potent anti-tumor activity in the mice harboring RNase7-expressing tumors. In addition, clinical data analysis indicated that ROS1 and RNase7 co-expression occurs in about 30% of HCC patients and is highly correlated with poorer survival. The plasma level of RNase7 is positively correlated with phosphorylated ROS1 in HCC patients. Our current report provides a rationale to choose RNase7 as a potential plasma biomarker to stratify HCC patients for anti-ROS1 targeted therapy. Citation Format: Chunxiao Liu, Zhengyu Zha, Chenhao Zhou, Dihua Yu, Ning Ren, Mien-Chien Hung. RNase7-guided anti-ROS1 targeted therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5286.
Abstract 1400: AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK
Authors: Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa
Journal: Cancer Research (2022)

Abstract Introduction: Bruton's tyrosine kinase (BTK) has been recently recognized as a validated drug target for the treatment of B-cell malignances. The emergence of clinical resistance to the first-generation covalent BTK inhibitors is, however, becoming a serious concern. Patients are reported to develop resistance during the treatment due to substitution of cysteine residue at position 481 with serine (C481S mutation) in BTK, which prevents the covalent binding of the first-generation irreversible BTK inhibitors, resulting in the loss of inhibitory activities. Therefore, there is a high unmet medical need for new therapeutic approaches to overcome the BTK C481S-mediated resistance. Material and methods: Compounds were tested in biochemical assays using recombinant human wildtype (WT) and C481S mutant BTKs. Cellular activity of AS-1763 was evaluated in human diffuse large B cell lymphoma (DLBCL) cell lines, OCI-Ly10 and its BTK[C481S] knock-in cells. The in vivo antitumor activity of AS-1763 was assessed in two tumor xenograft mouse models bearing WT or BTK [C481S] knock-in OCI-Ly10 cells. Results: We have discovered AS-1763 as an orally available, highly potent, selective and reversible BTK inhibitor. AS-1763 showed potent inhibitory activities for WT BTK (an activated form, BTK[A]) and the C481S mutant with sub-nanomolar IC50s (IC50 = 0.85 and 0.99 nM for BTK[A] and BTK[C481S], respectively). In cellular assays, AS-1763 exhibited strong antiproliferative activities for WT and BTK [C481S] knock-in OCI-Ly10 cells. AS-1763 demonstrated significant tumor growth inhibition and tumor regression in WT as well as BTK[C481S] knock-in OCI-Ly10 xenograft model. Conclusions: The preclinical data support the clinical development of AS-1763 in patients with B-cell malignancies both having WT and C481S mutation in BTK. The first-in-human Phase 1 clinical trial of AS-1763 in healthy volunteers (EudraCT 2020-005599-37) is currently ongoing, and the Phase 1b study in patients is expected to begin in 2022. Citation Format: Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa. AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1400.
Abstract 261: Released exosomes from colon cancer cells regulate formation and progression of perineural invasion
Authors: Colewyn Knoblich, Khosrow Rezvani
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the third most diagnosed cancer and cause of cancer related mortality. CRC that metastasizes to distance sites results in poor prognosis, diminished survival, and reduced effectiveness of treatments. Perineural invasion (PNI) is an emerging field that aims to understand cancer-neuronal crosstalk that enables cancer to spread via nerves. Several studies have indicated that tumor derived exosomes (TDEs) play significant roles in the initiation and spread of cancer, along with driving chemoresistance. We hypothesize that CRC derived exosomes alter nerves within the surrounding environment and result in recruitment of nerves towards tumors for invasion along the nerve. Exosomes from both HCT116 and SW837 colon cancer cells were isolated and purified using a modified iodixanol ultracentrifugation gradient technique. A Proteomic analysis conducted on cancer derived exosomes revealed several potential proteins involved in neuronal growth and migration, including Vinculin (VCL), Periostin (POSTN or OSF-2), DCLK1, and USP9X. In another set of experiments, conditioned media (CM) from HCT116 and SW837 cells were added to both PC12 neuronal-like cells and dorsal root ganglion (DRG) from C57BL/6J mice to understand the effects of excreted cancer factors on neuronal outgrowth and differentiation. CM studies showed how signaling factors excreted from colon cancer cells induce increased nerite outgrowth in both PC12 cells and DRG. These results were not seen in CM from cancer cells that were grown in the presence of an exosome inhibitor. Altogether, these results indicate that CRC utilizes exosomes to alter the adjacent neuronal networks as a means to employ surrounding nerves for invasion. Citation Format: Colewyn Knoblich, Khosrow Rezvani. Released exosomes from colon cancer cells regulate formation and progression of perineural invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 261.
Abstract 2935: Whole genome sequence of triple negative breast cancer (TNBC) tumors of African descent
Authors: Samuel Terkper Ahuno, Yajas Shah, Rachel Martini, Andrea Sboner, Nicolas Robine, Olivier Elemento, Marcin Imielinski, Lisa Newman, Melissa Davis
Journal: Cancer Research (2022)

Abstract In the US, BC incidence has recently converged among self-reported European Americans (EA) and African Americans (AA), however BC mortality remains approximately 40% higher among AA compared to EA and other SRR groups. The initial divergence in mortality curves between these groups occurred at the advent of hormone receptor (HR) targeted treatment options, unmasking the heterogeneity of BC diagnoses. Here, we present Whole Genomes Sequencing of 30 Triple Negative Breast Cancers of African women presenting to the clinics in New York. These were collected as part of the ICSBCS cohort to identify ancestry related mutational signatures including complex structural variants which could help better explain etiology of cancer in these population and that we may leveraged for treatment or prognostic purposes. Somatic mutational landscape included higher frequency of TP53 (73%), BRCA1 (40%), ATK1 (37%), CDH1(37%), and CTCF (33%). We confirmed African ancestry of patients through ADMIXTURE and observed (&amp;gt;70%) African ancestry. Comparison between our cohort and TCGA BRCA showed higher tumor mutational burden in our cohort which could be accounted for by greater sensitivity in our updated sequencing technology and analysis pipelines. Mutational signature analysis showed cosmic Signature 3 suggesting evidence of defective homologous recombination and signature 16 with unknown etiology. In addition, we also observed evidence deletions and structural variants such as rigma, pyrgo and typhonas. Ongoing efforts are investigating complex structural variants in our cohort compared to similar populations from other studies while waiting on additional samples. Citation Format: Samuel Terkper Ahuno, Yajas Shah, Rachel Martini, Andrea Sboner, Nicolas Robine, Olivier Elemento, Marcin Imielinski, Lisa Newman, Melissa Davis. Whole genome sequence of triple negative breast cancer (TNBC) tumors of African descent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2935.
Abstract 5364: The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical <i>EGFR</i> mutant tumor models
Authors: Tracy T. Tang, Leonard Post
Journal: Cancer Research (2022)

Abstract The Hippo-YAP/TAZ pathway is involved in the regulation of cell proliferation, survival, and cell migration. The major effectors of the Hippo pathway are the TEAD transcription factors, which become transcriptionally activated upon YAP/TAZ binding. Genetic alterations of pathway components have been reported in a variety of human malignancies, resulting in YAP/TAZ constitutive nuclear localization and TEAD activation. The TEAD transcription factors have been shown to autopalmitoylate, and palmitoylation is required for its interaction with YAP/TAZ and hence activation of transcriptional activity. We have identified potent, selective, and orally available small molecule compounds that directly interact with TEAD and block its autopalmitoylation (Tang et al, 2021, Mol Cancer Ther. 20(6):986-998). These TEAD inhibitors disrupt YAP/TAZ-TEAD protein interaction, suppress TEAD transcriptional activity, and selectively block proliferation of NF2-deficient mesothelioma in vitro and inhibit NF2 mutant xenograft tumor growth in vivo. Nuclear YAP accumulation and functional requirement have also been linked to resistance to targeted therapies and cancer relapse in BRAF-mutant, KRAS-mutant, EGFR-mutant, and ALK-rearranged non-small cell lung cancers (NSCLC). Hence, as TEAD transcription factors are the main drivers for YAP/TAZ recruitment to chromatin, we evaluated the effect of our TEAD inhibitor VT3989, currently in clinical testing, on emerging drug tolerant persistent cancer cells and drug resistance during EGFR-tyrosine kinase inhibitor osimertinib treatment in combination studies. In in vitro cell proliferation assays, VT3989 showed strong to very strong synergy in combination with osimertinib in several EGFR mutant NSCLC cell lines tested. In vivo, we observed strong VT3989 and osimertinib combination effect in NCI-H1975 and HCC827 cell line-derived xenograft models. We also tested the combination in several EGFR mutant NSCLC patient-derived xenograft models and demonstrated that the addition of VT3989 enhanced the efficacy of osimertinib and delayed tumor regrowth compared to osimertinib alone. Citation Format: Tracy T. Tang, Leonard Post. The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5364.
Abstract 6323: Differential analysis of HPV16-human and EBV1-human protein interaction networks to identify new protein candidates in head and neck squamous cell carcinomas
Authors: Arsalan Riaz, Yusra Ilyas, Faisal Khan
Journal: Cancer Research (2022)

Abstract Oro-pharyngeal squamous cell carcinoma (OPSCC) cases are rising worldwide specifically among young individuals with risk factors including smoking and alcohol. HPV infection specifically the subtype HPV16 is a significant risk factor in the initiation and progression of OPSCC, more prevalent in the western part of the world. This study carries out a computational analysis using protein interactions between HPV16 proteins and protein products of key OPSCC and Oral Squamous Cell Carcinoma (OSCC) cancer genes, which aims to investigate the influence of HPV16 on OPSCC and OSCC in terms of protein-protein interactions (PPIs).We created a protein interaction network of HPV16 and human proteins followed by retrieval of mutated genes in OPSCC and OSCC from online databases including COSMIC, cBioPortal and the GDC Portal, along with literature mining. We used MCODE and ClueGo tools for cluster and enrichment analysis, respectively. Drug candidates against the common interacted proteins were found using drug databases like PanDrugs and CLUE Repurposing. After annotating the HPV16-Human PPI network with proteins encoded by genes found to be mutated in both cancers, 31 proteins in OPSCC and 17 proteins in OSCC were in direct interaction with the viral proteins especially, E5, E6, and E7. The immediate network (of first neighbors only) appeared to be sparse, but after looking at the broader HPV16-Human network we found 5 highly connected modules, 4 of which were dominated by proteins encoded by genes mutated in OPSCC as compared to OSCC, indicating the influence of HPV16 on OPSCC. Based on module integrity and topological characteristics we identified 4 significant candidates for HPV16-driven OPSCC i.e. MYC, CREBBP, PML, and RB1 which are significantly enriched in cancer pathways. In the South Asian countries, Epstein Bar Virus type 1 (EBV-1) is a more prevalent risk factor for virus-driven Head and Neck Squamous Cell Carcinoma (HNSCC) as compared to HPV-16, however, knowledge regarding the EBV induced OPSCC and OSCC is scarce. We created a protein interaction network for EBV1 and Human proteins to analyze the topological characteristics especially of proteins encoded by genes mutated in HNSCC using the same methodology and we identified 5 candidate proteins i.e. EP300, CUL3, RB1, DDB1, and CREBBP for further in vitro validation. Citation Format: Arsalan Riaz, Yusra Ilyas, Faisal Khan. Differential analysis of HPV16-human and EBV1-human protein interaction networks to identify new protein candidates in head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6323.